Telomeres are specialized structures located at the ends of eukaryotic chromosomes consisting of simple DNA repeats and specific binding proteins, preventing degradation and end fusion. Recently, accelerated telomere shortening has been implicated in premature aging and also observed in Alzheimer's disease (AD). However, little is known about how telomeres are regulated in neurons during aging and how its deregulation contributes to the development of AD. Pin 1, a peptidyl-prolyl cis/trans isomerase, regulates protein function by isomerizing specific phosphorylated Ser/Thr-Pro bonds. Pin1-induced conformational changes after phosphorylation are important in many cellular processes, including neuronal survival. Significantly, Pin 1deregulation can play an important role In some pathological conditions such as premature aging and AD. My own preliminary data showed that Pin1 interacted with the conserved phosphorylated Thr149-Pro motif in the telomere DNA-binding protein TRF1, which is a major regulator of telomere length by limiting telomere elongation by telomerase when telomeres reach certain length. Furthermore, inhibition of Pin 1 rendered TRF1 resistant to degradation and also caused telomere shortening. Moreover, Pin 1 knockout in mice leads to elevated TRF1 levels, accelerated telomere shortening and a range of premature aging phenotypes within single generation, suggesting that Pin1 is a central regulator of TRF1 and telomere maintenance. These results led me to hypothesize that Pin 1-dependent regulation of TRF1 and telomere maintenance might play a major role in the development of aging and AD. In the mentored phase of this award, I plan to develop my skills in the administration of genetic material to the murine brain, focusing on the role of Pin1 in telomere maintenance in neurons during aging and AD using various mouse models available in my mentor's laboratory. In the independent phase of the award, I will investigate molecular mechanisms by which Pin 1 regulates TRF1 and telomere maintenance as well as by which Pin1 itself is regulated by phosphorylation during aging and AD. These studies should provide novel insight into telomere maintenance during aging and AD, and might have novel implications for developing new therapies. RELEVANCE: AD is the most common form of dementia, affecting millions people in the world and with only limited treatments. My goal is to identify novel molecular mechanisms leading to development of AD by focusing on telomere biology. This study will have a significant impact upon our basic understanding of AD, and might eventually facilitate the development of novel treatments of AD via targeting of telomere maintenance.